Curing Accelerator and Method of Making

ABSTRACT

The invention concerns sterilized cyanoacrylate adhesive compositions comprising 99% or more by weight, based on the weight of the adhesive composition, of 2-octyl cyanoacrylate, mixed together with butylated hydroxyl anisole, sulfur dioxide, and 100 to 1000 parts per million, based on the weight of the adhesive composition, of a 18-crown-6 crown ether, wherein the composition is sterilized by irradiation as well as methods of making and using such compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/230,351 filed Mar. 31, 2014, which is a continuation of U.S. patentapplication Ser. No. 11/767,565 filed Jun. 25, 2007, now U.S. Pat. No.8,729,121, issued May 20, 2014 the disclosures of each are incorporatedherein in their entireties.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

The present invention relates to cyanoacrylate adhesives. In particular,the present invention relates to cyanoacrylate adhesives with a supercure speed for medical use.

(2) Description of Related Art

Cyanoacrylate compositions have long been known in the art as excellentadhesives. The cyanoacrylate adhesives are liquid monomers thatpolymerize on contact with tissue surfaces in an exothermic reactioncreating a strong yet flexible film. The polymer film is generallyformed rapidly. Liquid cyanoacrylate compositions have found applicationin medicine for closing wounds and incisions, especially in cases wheresuturing does not provide satisfactory results because ofcyanoacrylate's unique ability to bond living tissue and their long-termbond strength. They have found wide applications as industrial andstructural adhesives, consumer products for repair of household itemsand in the hobby sector for assembly and repair.

It is well known that cyanoacrylate adhesive compositions are verysensitive and careful handling is required to prepare theirformulations. In order to extend the applications of cyanoacrylateadhesives, a variety of additives have been incorporated in theirformulations including stabilizers, viscosity modifiers, thixotropicagents, plasticizers, biocompatible agents, and polymerizationactivators.

Cyanoacrylate polymerization is usually considered as the result of ananionic initiation with water being a sufficiently strong base. In spiteof the relatively fast cure speed of cyanoacrylate adhesives,polymerization enhancers have to be incorporated for specificapplications. First, the cure speed would be drastically dropped ifcyanoacrylate adhesives were applied to the acidic substrates such aswood and paper. In this case, the cyanoacrylate adhesives with a fastercure time would offer an option. In addition, a relatively large amountof cyanoacrylate applied in certain cases will result in the slowerhardening throughout the adhesives. However, a better cure-through-gapperformance should be attained if a faster curing cyanoacrylateformulation is used.

In order to enhance the polymerization rate for such applications, anumber of efforts have been made by applying accelerators throughdifferent methods. For example, a two component system has been used bypackaging the cyanoacrylate adhesive and the accelerator separately. Thecure speed of cyanoacrylate adhesives is improved. The disadvantage ofthis method is that the accurate measurement and mixing two componentshomogenously are very difficult tasks to achieve since only a tinyamount of accelerators is generally required.

As an example, U.S. Pat. No. 5,928,611 to Leung discloses an applicatortip for dispensing a polymerizable material, in which a polymerizationaccelerator was included. The accelerator initiates polymerization whenthe polymerizable material is dispensed through the applicator tip.Suitable accelerators include detergent compositions; surfactants,amines, urea, phosphines, alcohols, inorganic bases and salts, sulfurcompounds, polymeric cyclic ethers, crown ethers, calixarenes, cyclicand acyclic carbonates, organometallics, and radical. The polymerizablematerial may also contain an initiator which is inactive until activatedby a catalyst in the applicator tip. Initiators activated by stimulationsuch as heat and/or light are also suitable if the tip and/or applicatoris appropriately subjected to such stimulation.

U.S. Pat. Application No. 20050196431 to Narang et al. discloses anapplicator tip for an applicator for applying a polymerizable monomericadhesive composition that can include a bioactive material, a flavorant,a polymerization initiator, and/or a polymerization rate modifier. Ithas been discovered that the use of methanol, alone or as a component ofa mixture of low boiling point solvents, to apply a polymerizationaccelerator to an applicator tip used to dispense monomer-containingadhesive compositions, provides an unexpectedly superior distributionprofile of the material on, and within, the applicator tip. Applicatortips according to their invention can control the setting time of thepolymerized or cross-linked adhesive, extend the shelf life of themonomer and control the flow properties of applied cyanoacrylateadhesives.

U.S. Pat. No. 4,460,759 to Narang discloses two-component adhesivecompositions. One component contains the cyanoacrylate monomer and thesecond component contains a weakly acidic or weakly basic ionicaccelerator consisting of a cation having a pKa of at least 10 and anucleophilic anion.

Another approach to enhance the cure speed of cyanoacrylate adhesive isto apply the diluted solutions of the accelerators in low-boiling pointsolvents to the cyanoacrylate adhesives. The accelerator solutions canbe added to the substrate in advance or applied when the cyanoacrylateadhesive is still liquid. Japanese Patent Application No. JP-A-03 207778 discloses the use of solutions of aliphatic, alicyclic and,especially, tertiary aromatic amines as the activators for the curing ofcyanoacrylate adhesives. Specific examples includedN,N-dimethylbenzylamine, N-methylmorpholine and N,N-diethyltoluidine.Japanese Patent Application No. JP-A-62 022 877 suggested the use ofsolutions of lower fatty amines, aromatic amines, and dimethylamine forthe same purpose.

British Patent Specification No. 1 230 560 described cyanoacrylateadhesive compositions containing certain substituted heterocycliccompounds as accelerators. The compositions may be presented in atwo-part form, the first part comprising the cyanoacrylate adhesive andthe second part comprising at least one of the substituted heterocycliccompounds, preferably dissolved in an organic solvent. The heterocycliccompound is invariably present in one part of a two-part compositionbecause iminoethylene-substituted triazines and pyrimido-pyrimidinesaccelerat the polymerization so rapidly that they must be kept apartfrom the cyanoacrylate composition before use. An effective adhesivebond is obtained. However it is not concerned with an activator which isable to initiate polymerization throughout a layer of adhesive.

U.S. Pat. No. 3,260,637 to von Bramer discloses the use of a range oforganic amines as accelerators for cyanoacrylate adhesives, particularlyfor use on metallic and non-metallic substrates. According to theinvention, a catalyst solution comprising one or more organic amines wasemployed in a suitable solvent to moisten the surfaces to be bonded andto catalyze the adhesive action of cyanoacrylate adhesive composition.

U.S. Pat No. 4,042,442 to Dombroski et al. discloses the addition of apolymerization initiator such as caffeine and theobromine to acyanoacrylate adhesive composition. The caffeine or theobromine is addedto the adhesive composition in different ways. Firstly, the caffeine ortheobromine is dissolved in a volatile solvent, applied to the surfacesto be joined, the volatile solvent is allowed to evaporate, and then thecyanoacrylate adhesive composition is applied to the surfaces of thesubstrates to be joined. Secondly, the caffeine or theobromine can bemixed with the cyanoacrylate adhesive composition by stirring just priorto application of the adhesive to the substrates to be joined. Both ofthese methods are inconvenient for the user because two separatesolutions or two separate applications are required.

U.S. Pat No. 5,561,198 to Huver provided an activator for cyanoacrylateadhesives based on N, N-dialkyl aniline derivatives. The activators arecharacterized by a molecular weight of more than 200 and by at most 3carbon atoms for both N, N-dialkyl substituents together. Theirinvention also provided methods of production and use of the activatorand to the combination product of the activator and the cyanoacrylateadhesive. In their inventions, the activators were tested according tocriteria including reactivity, cure rate on activated aluminum teststrips, cure rate after activation, tensile shear strength onsand-blasted aluminum strips, transparency, and odor of the reactivity.

U.S. Pat. No. 6,547,917 to Hanns et al. revealed the accelerated curingof cyanoacrylate adhesives using organic compounds containing thestructural element —N═C—S—S—C═N— in dilute solution as activators.Examples of such compounds include 6,6′-dithiodinicotinic acid,dibenzodiazyl disulfide, 2,2′-dipyridyl disulfide orbis(4-t-butyl-1-isopropyl-2-imidazolyl) disulfide. According to theirinvention, the activators are dissolved in readily volatile solvents,such as hydrocarbons, carboxylic acid esters, ketones, ethers orhalogenated hydrocarbons. The activator solutions according to theirinvention are suitable for the accelerated curing of all conventionalcyanoacrylate adhesives which contain as the fundamental constituent oneor more cyanoacrylic acid esters, inhibitors of free-radicalpolymerization, inhibitors of anionic polymerization and, optionally,conventional auxiliary substances employed in such adhesive systems. Ascompared with the known accelerators, their method provided thefollowing advantage: good accelerating action, but they neverthelessrequire a long waiting time between application of the activator andapplication of the adhesive.

U.S. Pat. No. 6,995,227 to Ryan et al. discloses an activatorcomposition for the accelerated curing of cyanoacrylate adhesives,wherein the activator comprises a member selected from the groupconsisting of: aromatic heterocyclic compounds having at least one Nhetero atom in the ring(s) such as pyridines, quinolines and pyrimidinesand substituted on the ring(s) with at least one electron-withdrawinggroup which decreases the base strength of the substituted compoundcompared to the corresponding unsubstituted compound, mixtures of any ofthe foregoing with each other, and/or with N,N-dimethyl-p-toluidine, andmixtures of any of the foregoing and/or N,N-dimethyl-p-toluidine with anorganic compound containing the structural element, such asdibenzothiazyl disulfide, 6, 6′-dithiodinicotinic acid, 2,2′-dipyridyldisulfide, and bis(4-t-butyl-1-isopropyl-2-imidazolyl)disulfide. Anactivator composition may comprise a solution of one or more activatorsin a solvent mixture which comprises a volatile hydrocarbon and a cyclicketone. Their invention reduced the problem of “halo” effect andprovided activator solutions with different properties.

In order to improve the cure speed of cyanoacrylate adhesives, anotherimportant method is to incorporate accelerators directly to the adhesiveformulations. DE-A-40 09 621 proposed the use of certain cyclodextrinderivatives as an additive to improve the cure speed of cyanoacrylateadhesive, some of which are soluble in cyanoacrylates. GB-A-2 200 124revealed the use of acyclic phenol-formaldehyde oligomers as anaccelerating additive for cyanoacrylate adhesive formulations.

German patent DE-A-22 61 261 proposed accelerator substances containingthe structural element-N═C—S—. According to their invention,cyanoacrylate adhesives containing such accelerators do in fact showthat even relatively large amounts of adhesive harden relatively rapidlyand reliably. However, that compound has a very high volatility, so thatactivator solutions based thereon are unsuitable for applicationbeforehand since the active ingredient also evaporates off with thesolvent.

U.S. Pat. No. 4,386,193 to Reich, et al. discloses a rapid-setting.alpha.-cyanoacrylate based adhesive composition having good storagestability and, in particular, to an adhesive composition having a veryfast setting time on wood and other substrates with a parous/acidsurface by using 3 or 4 arm polyol podand compounds as accelerators.

Japanese Patent Application No. 59-66471 discloses amine derivatives asa curing accelerator of cyanoacrylate adhesives. The amine compoundshave a boiling point of between 50° C. and 250° C. Examples of suitableamines include propanolamine triethylamine, diethylamine, isopropylamine, butyl amine, tributyl amine, N,N-dimethyl-o-toluidine,N,N-dimethyl aniline, N,N-diethyl aniline, N,N-dimethyl-p-toluidine,N,N- dimethyl-m-toluidine dimethyl benzyl amine, pyridine, picaline,vinyl pyridine, ethanolamine, and ethylene diamine

U.S. Pat. No. 4,377,490 to Shiraishi et al., discloses mixtures ofaromatic and aliphatic polyols and polyethers to improve initialstrength of cyanoacrylate wood bonding products.

European Patent Specification No. 0 271 675 A2 discloses a primer forcyanoacrylate resin compositions for use in bonding non-polar or highlycrystallized resins such as polyolefins, polyethyleneterephthalates,nylons, fluorine-containing resins, and soft PVC films. The primercomprises (i) an organic amine and (ii) a compound selected from thegroup consisting of benzene ring compounds having aldehyde group andnitrogen or oxygen atom-containing heterocyclic compounds havingaldehyde group. The specification states that a cyanoacrylate adhesiveexhibited a strong bonding strength at ambient temperature.

U.S. Pat. No. 4,718,966 to Stephen, et al. discloses cyanoacrylateadhesive compositions which employ calixarene compounds as acceleratorsgive substantially reduced fixture and cure times on deactivatingsubstrates such as wood, leather, ceramic, plastics and metals. Thecalixarene compounds are preferably employed at levels of about 0.1-1%by weight of the composition.

In U.S. Pat. No. 4,170,585 to Motegi et al., certain polyethyleneglycols poly(ethyleneoxy) functional are disclosed to be additives forincreasing the curing speed of cyanoacrylate compositions. Suchcompounds, however, have the reported disadvantage that they containwater and other substances difficult to remove which spontaneouslyinitiate polymerization of the cyanoacrylate monomer.

Japanese Patent Application No. 8-310136 to Ohashi, et al. discloses2-cyanoacrylate adhesive compositions containing a crown ether curingaccelerator or a polyalkylene oxide curing accelerator. However, thesecompositions are not suitable for medical applications.

In general, cyanoacrylate combinations with accelerators have beenobtainable by separately housing the cyanoacrylate and accelerator. Thecyanoacrylate is then flowed past the accelerator housing to add theaccelerator to the cyanoacrylate. This method is used for industrialapplications, where large batches of the cyanoacrylate are needed. Thismethod is not suitable for medical use, nor are the cyanoacrylatecompositions prepared from this method amenable to being sterilized inpreparation for medical use.

Based on the descriptions above, different design systems and a varietyof chemicals have been applied to accelerate the curing speed ofcyanoacrylate adhesives. However, most of the employed acceleratorsexhibited their own shortcomings at different extents. Some of them aremore toxic, while others exhibit weak activation, less bond strength,high volatility and odor. In addition, irregular structure is formed insome cases, which destroys transparency of film. These disadvantagesthus limit the application of cyanoacrylate adhesives in differentfields, especially for medical use. The goal of the present inventionis, therefore, to develop a new accelerating agent for cyanoacrylateadhesives, which is particularly suitable for medical applications.

BRIEF SUMMARY OF THE INVENTION

The present invention provides for a sterilized cyanoacrylate adhesivecomposition including a cyanoacrylate composition and a cure speedenhancer, wherein the sterilized cyanoacrylate adhesive composition doesnot cure upon sterilization.

The present invention also provides for a kit for applying thesterilized cyanoacrylate adhesive composition, including thecyanoacrylate adhesive composition and an applicator.

The present invention provides for a method of making the sterilizedcyanoacrylate adhesive composition by adding a cure speed enhancer to acyanoacrylate adhesive composition and sterilizing the composition.

The present invention further provides for a method of applying thesterilized cyanoacrylate adhesive composition to tissue by applying thesterilized cyanoacrylate adhesive composition as a liquid, and quicklycuring the sterilized cyanoacrylate adhesive composition.

The present invention also provides for a method of sealing tissue byapplying the sterilized cyanoacrylate adhesive composition as a liquidto tissue to be sealed, quickly curing the sterilized cyanoacrylateadhesive composition, and sealing the tissue.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention provides for a sterilized cyanoacrylate adhesivecomposition and method of preparing the same including a cure speedenhancer added to a cyanoacrylate adhesive composition. The sterilizedcyanoacrylate adhesive composition is essentially a bioabsorbable tissueadhesive for sealing and aiding in the repair of tissue. Importantly,the sterilized cyanoacrylate adhesive composition does not cure uponsterilization.

It is the goal of the present invention to provide a sterilizedcyanoacrylate adhesive composition with a very fast curing speed. Thisis achieved by including a cure speed enhancer, preferably 18-crown-6,which is a crown ether, in the preferable amount of 100-1600 ppm, to thecyanoacrylate adhesive composition before sterilization of thecomposition. Any other suitable cure speed enhancer, such as, but notlimited to, another crown ether, can also be used. The cure time ofcyanoacrylate composition can be improved up to 2-5 times depending uponthe amount of the accelerator applied. The cure speed enhancer issoluble in the cyanoacrylate monomer at room temperature. Thecompositions produced, packaged and sterilized according to the currentinvention have a much faster cure speed compared to cyanoacrylateadhesive compositions of the prior art.

The reason crown ether was chosen as the preferred cure speed enhancer,or accelerating agent, for cyanoacrylate adhesive is not only due to itsexcellent activation for curing. Although crown ethers are not known topossess medicinal properties themselves, they may improve drug uptakeand transport properties. For example, crown ethers affected the uptakeof pirarubicin by drug-resistant cells. (Biochem. Pharmacal. 1995, 50,2069-2076; Curr. Med. Chem. 2001, 8, 51-64). The special complexingproperties of crown ethers have led to applications in drug deliverysystems and as targeting functionalities incorporated in drugderivatives and DNA-binding agents. It was shown in DNA binding studiesthat the positive charge of cation-crown ether complexes increases theaffinity of crown ether linked compounds with the polyanionic phosphatebackbone of DNA. Thus, crown ether derivatized drugs may gain anincreased interaction with DNA by the formation of cationic complexeswith ions that are abundant in cells, such as sodium or potassium. (Int.J. Pharm. 1997, 159,207-213.; Int. J. Pharm. 1998, 172, 33 -70; Bioorg.Med. Chem. Lett. 1994, 4, 1123-1126.)

Another object of the present invention is to maintain, if not improve,the stability of cyanoacrylate adhesive compositions. As the cure speedof cyanoacrylate adhesive compositions has been dramatically improvedherein, the stability of the adhesive is still conserved. Such stabilityof the adhesive is sustained due to the following treatments: (a)reducing the amount of contaminants and extraneous additives by applyingthe particulate agent, (b) providing a stable cyanoacrylate adhesivecomposition by use of the combination of free radical stabilizer andanionic stabilizing agent and (c) further stabilizing the cyanoacrylateadhesive composition by applying more anionic stabilizer. Even with thepresence of the cure speed enhancer, the cyanoacrylate adhesivecomposition does not actually cure until it has been applied to tissue.

The stability of the cyanoacrylate adhesive composition with the curespeed enhancer is confirmed by both real time and accelerated aging testdetailed in the Examples below. Both the set time and viscosity dataindicate the stability of the said cyanoacrylate adhesive composition,also detailed below.

The amount of cure speed enhancer that is added to the monomercomposition depends upon the original cure speed of cyanoacrylatemonomer. The cure speed enhancer is preferably present in the amount ofabout 2-3200 ppm by weight of the adhesive composition. In preferredembodiments, the cure speed enhancer is present in the amount of about40-1600 ppm, and more preferably about 100-1000 ppm of the adhesivecomposition. The amount of the cure speed enhancer to be used can bedetermined by one of ordinary skill in the art using known techniqueswithout undue experimentation.

Preferably, the cyanoacrylate adhesive composition contains 2-octylcyanoacrylate. The cyanoacrylate composition can have a composition asdescribed in U.S. Provisional Application Nos. 60/858,853 and60/892,357, i.e. a blend of cyanoacrylate with a low molecular weightpolyether such as polyethylene glycol (PEG). The exact percentage ofeach of the components can be readily determined by one skilled in theart. The cyanoacrylate composition is bioabsorbable and degrades in thebody.

The cyanoacrylate adhesive composition has a viscosity in the range from2.5 to 70 centipoise, and preferably 5-30 centipoise, as measured with aBrookfield Viscometer at 25° C. Additionally, the viscosity of thecomposition should be maintained or increased by a controlled andacceptable amount after sterilization.

The cure time of cyanoacrylate adhesives in the absence of the curespeed enhancer is up to 90 seconds depending upon the amount of freeradical and anionic stabilizers included. However, the cure speed isdramatically increased after applying the cure speed enhancer to thecyanoacrylate composition. An increase of up to a few seconds can beachieved depending on the amount of the cure speed enhancer applied.

According to embodiments of the present invention, the stability, andthus the shelf-life, of the cyanoacrylate adhesive compositions in thepresence of the cure speed enhancer can be maintained during theaccelerated aging, the packaging and sterilizing procedures. Inpreferred embodiments, there is substantially no initiation ofpolymerization of monomeric liquid adhesive compositions that affectsthe utility of the monomer caused by the sterilization process.

The accelerated aging test of cyanoacrylate adhesive composition wasperformed in the oven at 80° C. for a period of 12 days. Based on thecalculation, 12 days accelerated aging at 80° C. is equal to 2 years ofshelf life, and 1 day of accelerated aging at 80° C. is equal to 60.8days. Throughout the entire aging procedure, all cyanoacrylate adhesivesamples remained fluid consistency and in good color. The stability ofthe aged cyanoacrylate adhesive samples was confirmed by set time andviscosity test.

The viscosity of the cyanoacrylate adhesive composition with the curespeed enhancer increased as the accelerated aging proceeded but theviscosity of the aged sample after day 12 was in the acceptable range.As an example, the average viscosity of cyanoacrylate adhesivecomposition in the presence of the cure speed enhancer at acceleratedaging day 0, day 3, day 6, day 9, and day 12 was 4.29, 5.72, 10.6, 25.5,and 53.1 centipoise, respectively.

The cure time of the cyanoacrylate adhesive composition with cure speedenhancer varied a little after the 12 days aging at 80° C. However, thecure time of the cyanoacrylate adhesive composition in the absence ofthe cure speed enhancer might be dropped a lot during the acceleratedaging process. For example, the average set time of one adhesive madefrom 2-octyl cyanoacrylate was increased from 40 seconds before theaccelerated aging to 65 and 112 seconds at day 6 and day 12,respectively.

The preferred free radical stabilizer included in the cyanoacrylateadhesive composition is butylated hydroxyl anisole (BHA), and thepreferred anionic vapor phase stabilizer is sulfur dioxide. However, anyother suitable free radical stabilizer and anionic vapor phasestabilizer can be used that are known in the art. The amount of anionicvapor phase stabilizer that is added to the monomer composition dependson the amount of cure speed enhancer applied, the monomer to bestabilized, as well as the packaging material to be used for thecomposition. Preferably, the anionic vapor phase stabilizer is added togive a concentration of less than 20 parts per million (ppm). The amountto be used can be determined by one of ordinary skill in the art usingknown techniques without undue experimentation.

Vinyl pyrrolidone polymers and copolymers can be applied to reduce theamount of contaminants and extraneous additives in the resultingadhesives from the cyanoacrylate adhesive formulation. These particulateagents are combined with the monomer adhesive in mutual contact untilthe adhesive is destabilized, whereupon the adhesive becomes isolatedfrom the destabilizing agent by various means such as to effectisolation of the adhesive from the destabilizing component. It is only arequisite that enough excess stabilizer is left behind so as to providethe desirable speed of cure.

The purity of cyanoacrylate adhesive compositions was checked by GC-MS.More than 99% of the adhesive composition is 2-octyl cyanoacrylate. Noplasticizer or thixotropic agent is incorporated in the saidcyanoacrylate adhesive composition.

The cyanoacrylate adhesive compositions are sterilized. This is onenovel aspect of the invention, as prior cyanoacrylate compositions withaccelerators were not sterilized for medical use. The sterilization canbe accomplished by common techniques, and is preferably accomplished bymethods including, but not limited to, chemical, physical, andirradiation methods. Examples of chemical methods include, but are notlimited to, exposure to ethylene oxide. Examples of irradiation methodsinclude, but are not limited to, gamma irradiation, electron beamirradiation, and microwave irradiation. Preferred methods are chemicalsterilization and electron beam sterilization. Also, the cyanoacrylatecompositions can be sterilized with ultraviolet (UV) radiation. Further,upon sterilization with any of these methods, the cyanoacrylate adhesivecompositions are not cured. In other words, curing does not occur untilapplication to tissue.

The sterility of the cyanoacrylate monomer composition with the curespeed enhancer was analyzed by Bacteriostasis and Fungistasis tests. Thetest sample consisted of the sample with a puncture created to allow theliquid inside of the sample to mix with the test media. All wereimmersed into 500 ml of Soybean Casein Digest Medium (SCDM). The testmicroorganism such as Bacillus subtilis, Candida albicans, andAspergillus niger, at less than 100 colony forming units, was inoculatedinto each of the test sample containers and into a positive controlcontainer of the same medium. After inoculation, the test sample andpositive control container were incubated at 20-25° C. for a five daymaximum incubation period. The growth of Bacillus subtilis, Candidaalbicans, and Aspergillus niger was observed for the said cyanoacrylateadhesive before the sterilization, while the said adhesives aftersterilization exert a gross fungistatic effect on Bacillus subtifis,Candida albicans, and Aspergillus niger.

Bond strength and wound closure were analyzed for the cyanoacrylateadhesive composition with the cure speed enhancer. The average bondstrength from tensile shear method (metal to metal) for the compositionsis 107.86 lbs/cm² with a standard deviation 13.03 lbs/cm².

In vivo biomechanical evaluation was performed using the rat linearincision wound model in order to assess and evaluate the efficacy of thecyanoacrylate composition with the cure speed enhancer as a new topicalsurgical tissue adhesive for the application of incisional woundclosure. For direct comparison, the commercially available productDermabond was also evaluated. The male Sprague-Dawley rat was chosen asthe animal model and this animal model has been used extensively forincisional wound strength studies, which has been well documented in theliterature. All study animals were acclimatized to their designatedhousing for approximately 7 days prior to the day of treatment. Prior tosurgery, final selection of the animals was based on a visual appraisalof good clinical condition, and body weight specifications.

TABLE 1 Biomechanical wound strength results for the cyanoacrylateadhesive with the cure speed enhancer and Dermabond. Study Date TimePoint Animal Study Group Group Description Side L/R May 8, 2006 acute 1A DERMABOND* HV (Lot# 125241 Exp. 2007-12) L May 8, 2006 acute 2 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) R May 8, 2006 acute 3 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) L May 8, 2006 acute 4 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) R May 8, 2006 acute 5 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) L May 8, 2006 acute 6 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) R May 8, 2006 acute 7 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) L May 8, 2006 acute 8 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) R May 8, 2006 acute 9 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) L May 8, 2006 acute 10 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) R May 8, 2006 acute 11 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) L May 8, 2006 acute 12 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) R May 8, 2006 acute 13 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) L May 8, 2006 acute 14 ADERMABOND* HV (Lot# 125241 Exp. 2007-12) R May 8, 2006 acute 1 B SpartanMedical Liquid Advesive Bandage (Lot# 327) R May 8, 2006 acute 2 BSpartan Medical Liquid Advesive Bandage (Lot# 327) L May 8, 2006 acute 3B Spartan Medical Liquid Advesive Bandage (Lot# 327) R May 8, 2006 acute4 B Spartan Medical Liquid Advesive Bandage (Lot# 327) L May 8, 2006acute 5 B Spartan Medical Liquid Advesive Bandage (Lot 327) R May 8,2006 acute 6 B Spartan Medical Liquid Advesive Bandage (Lot 327) L May8, 2006 acute 7 B Spartan Medical Liquid Advesive Bandage (Lot 327) RMay 8, 2006 acute 8 B Spartan Medical Liquid Advesive Bandage (Lot# 327)L May 8, 2006 acute 9 B Spartan Medical Liquid Advesive Bandage (Lot#327) R May 8, 2006 acute 10 B Spartan Medical Liquid Advesive Bandage(Lot# 327) L May 8, 2006 acute 11 B Spartan Medical Liquid AdvesiveBandage (Lot# 327) R May 8, 2006 acute 12 B Spartan Medical LiquidAdvesive Bandage (Lot# 327) L May 8, 2006 acute 13 B Spartan MedicalLiquid Advesive Bandage (Lot# 327) R May 8, 2006 acute 14 B SpartanMedical Liquid Advesive Bandage (Lot# 327) L Date Wound SizeTerminationWeight (g) Ultimate Pressure (mmHg) Comments May 8, 2006 1275 271 May 8, 2006 1 297 230 May 8, 2006 1 286 291 May 8, 2006 1 285163 May 8, 2006 1 290 226 May 8, 2006 1 297 169 May 8, 2006 1 280 162May 8, 2006 1 277 200 May 8, 2006 1 294 161 May 8, 2006 1 284 276 May 8,2006 1 282 320 May 8, 2006 1 287 105 May 8, 2006 1 280 326 May 8, 2006 1205 372 Mean 255.5 240.0 St. Dev. 5.3 70.1 May 8, 2006 1 275 210 May 8,2006 1 297 220 May 8, 2006 1 286 164 May 8, 2006 1 285 215 May 8, 2006 1290 119 May 8, 2006 1 287 274 May 8, 2006 1 280 314 May 8, 2006 1 277243 May 8, 2006 1 294 251 May 8, 2006 1 284 235 May 8, 2006 1 282 291May 8, 2006 1 287 261 May 8, 2006 1 280 285 May 8, 2006 1 292 175 Mean255.5 231.7 St. Dev. 6.3 52.5 p-value ANOVA (p = 0.05) 0.736201604

The animals were anesthetized, placed on a surgical table with awater-heating pad, and prepped with Betadine surgical skin prep and 70%alcohol solution. To control incision length and location, a templateand surgical skin-marking pen were used to mark two symmetric 0.75-inchlinear incisions over each dorsolateral flank area. All animalsunderwent the same surgical procedure. All incisions were made by thesame surgeon and extend through the skin, subcutaneous tissue andpanniculus carnosus. The incisional wounds were then biomechanicallytested for incisional wound strength.

A BTC disposable acrylic test ring (ID 2.5 em) was placed around thewound and secured to the skin using cyanoacrylate adhesive with the curespeed enhancer or commercially available Dermabond. A small amount ofperfluorinated grease was applied to the top of the ring interface toassure a tight vacuum seal. The BTC-2000™ test chamber was integratedwith the test ring until the chamber and ring were securelyinterconnected. The test chamber was held by hand comfortably to assurethat no positive force was being exerted on the wound. A constantnegative pressure was applied to the wound at a rate of 10 mmHg/second,producing a multi-axial stress on the wound. A displacement lasercaptured displacement of wound margins.

Based on the wound strength raw data presented in Table 1, the averageultimate pressure applied in wound site for the said cyanoacrylateadhesive and the commercial Dermabond was in the same level, indicatingthe cyanoacrylate with the cure speed enhancer possesses a bond strengthstrong enough to be used for wound closure as a medical product.

In vitro cytotoxicity of the cyanoacrylate adhesive with the cure speedenhancer was evaluated. For comparison, the commercially availableproduct Dermabond was also evaluated. A 2 cm² sterile disc of filterpaper was saturated with 2-octylcyanoacrylate adhesive composition withthe cure speed enhancer prior to dosing. L 929 mammalian fibroblastcell, seeded at a density of about 100,000 cells per mL at 7 mL per60×15 mm plate, were allowed to propagate in serum supplemented minimumessential medium in a single test plate until greater than 80%confluence was observed. Growth generally requires about 48 to 72 hoursin a humidified carbon dioxide incubator at 37±1° C. When the cellculture reached confluence, the growth media was removed aseptically andtriplicate plates were refilled with serum supplemented culture mediacontaining not more than 2% agar overlay. The flat surface of thecyanoacrylate adhesive sample, positive and negative controls, and mediacontrol was then placed in contact with solidified agar surface. Thetest plates were then returned to the incubator for 24 hours. At the endof the additional incubation, the plates were individually observedunder an inverted light microscope for signs of cell toxicity. The testresults (Table 2) indicated that only minimal cytotoxicity was observedfor the cyanoacrylate adhesive with the cure speed enhancer, whileminimal to mild cytotoxicity was observed for the control Dermabond.

TABLE 2 Results of test for in vitro cytotoxicity. Test articleEva!uation of cytotoxicity The said adhesive ±, ±, ± Dermabond ±, ±, 1USP HOPERS 0, 0, 0 (Negative control} USP Bioreaction RS 2,2,2 (Positivecontrol) Media Control (MEM) 0, 0, 0 Ratings 0 Noncytotoxic Nodetectable zone around or under specimen ± Slight Some malformed ordegenerated cytotoxic cells under specimen 1 Mildly Zone limited to areaunder cytotoxic specimen 2 Moderate Zone extends 0.5 to 1.0 cm cytotoxicbeyond specimen 3 Severely Zone extends greater than 1.0 cm cytotoxicbeyond specimen

The above results of the in vivo biomechanical evaluation using the ratlinear incision wound model revealed that the cyanoacrylate adhesive hascomparable bond strength as the commercial product Dermabond. Inaddition, in vitro cytotoxicity provided additional evidence that thecyanoacrylate adhesive is more suitable for medical use. Thecyanoacrylate adhesive exhibits only minimally cytotoxicity, whileminimally to mild cytotoxicity was observed for the control Dermabond.Therefore, the cyanoacrylate adhesive of the present invention hasadvantages over the prior art.

The cyanoacrylate composition of the present invention can be used inconjunction with the inventions disclosed in U.S. ProvisionalApplication No. 60/858,853 and 60/892,357, incorporated by referenceherein. For example, the cyanoacrylate composition of the presentinvention can be used in conjunction with therapeutic-loadednanoparticles to provide further therapeutic relief.

The cyanoacrylate compositions of the present invention are especiallysuitable for use in medical applications. In use, the cyanoacrylateadhesive composition is applied to the desired tissue area as a liquidwhich then polymerizes upon contact with tissue. The cure speed enhancerallows for quick polymerization and setting of the cyanoacrylateadhesive composition, i.e. quick curing. The polymerized patch ofcyanoacrylate adhesive allows the tissue to heal properly. Over time,water is drawn into the adhesive, causing it to degrade. The componentsof the adhesive then are cleared from the body.

The present invention further provides for a kit for applying thecyanoacrylate adhesive composition of the present invention, includingan applicator containing therein an effective amount of thecyanoacrylate composition. The applicator can be any suitable applicatorsuch as, but not limited to, Q-tips, a swab, or an applicator tip on acontainer with the cyanoacrylate composition therein. The kit canfurther contain directions for application. When the present inventionis used with other therapeutics, separate containers can be provided forthe cyanoacrylate composition and the therapeutic for application.

Individual applicators can be packaged separately to maintain sterileconditions. For example, each applicator can be packaged in plastic orany other suitable enclosing material. Multiple applicators can then bepackaged in a box for shipping.

The compound of the present invention is administered and dosed inaccordance with good medical practice, taking into account the clinicalcondition of the individual patient, the site and method ofadministration, scheduling of administration, patient age, sex, bodyweight and other actors known to medical practitioners. Thepharmaceutically, “effective amount” for purposes herein is thusdetermined by such considerations as are known in the art. The amountmust be effective to achieve improvement including but not limited toimproved survival rate or more rapid recovery, or improvement orelimination of symptoms and other indicators as are selected asappropriate measures by those skilled in the art.

In the method of the present invention, the compound of the presentinvention can be administered in various ways. It should be noted thatit can be administered as the compound and can be administered alone oras an active ingredient in combination with pharmaceutically acceptablecarriers, diluents, adjuvants and vehicles. The compounds can beadministered in any suitable way. Implants of the compounds are alsouseful. The patients being treated are warm-blooded animals and, inparticular, mammals including human beings. The pharmaceuticallyacceptable carriers, diluents, adjuvants and vehicles as well as implantcarriers generally refer to inert, nontoxic solid or liquid fillers,diluents or encapsulating material not reacting with the activeingredients of the invention.

The doses can be single doses or multiple doses over a period of severaldays. The treatment generally has a length proportional to the length ofthe disease process and drug effectiveness and the patient species beingtreated.

When administering the compound of the present invention parenterally,it will generally be formulated in a unit dosage injectable form(solution, suspension, emulsion). The pharmaceutical formulationssuitable for injection include sterile aqueous solutions or dispersionsand sterile powders for reconstitution into sterile injectable solutionsor dispersions. The carrier can be a solvent or dispersing mediumcontaining, for example, water, ethanol, polyol (for example, glycerol,propylene glycol, liquid polyethylene glycol, and the like), suitablemixtures thereof, and vegetable oils.

Proper fluidity can be maintained, for example, by the use of a coatingsuch as lecithin, by the maintenance of the required particle size inthe case of dispersion and by the use of surfactants. Nonaqueousvehicles such a cottonseed oil, sesame oil, olive oil, soybean oil, cornoil, sunflower oil, or peanut oil and esters, such as isopropylmyristate, may also be used as solvent systems for compoundcompositions. Additionally, various additives which enhance thestability, sterility, and isotonicity of the compositions, includingantimicrobial preservatives, antioxidants, chelating agents, andbuffers, can be added. Prevention of the action of microorganisms can beensured by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol, sorbic acid, and the like. In manycases, it will be desirable to include isotonic agents, for example,sugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, for example, aluminum monostearate and gelatin.According to the present invention, however, any vehicle, diluent, oradditive used would have to be compatible with the compounds.

Sterile injectable solutions can be prepared by incorporating thecompounds utilized in practicing the present invention in the requiredamount of the appropriate solvent with various of the other ingredients,as desired.

A pharmacological formulation of the present invention can beadministered to the patient in an injectable formulation containing anycompatible carrier, such as various vehicles, adjuvants, additives, anddiluents; or the compounds utilized in the present invention can beadministered parenterally to the patient in the form of slow-releasesubcutaneous implants or targeted delivery systems such as monoclonalantibodies, vectored delivery, iontophoretic, polymer matrices,liposomes, and microspheres. Examples of delivery systems useful in thepresent invention include those disclosed in U.S. Pat. Nos. 5,225,182;5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194;4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other suchimplants, delivery systems, and modules are well known to those skilledin the art.

While specific embodiments are disclosed herein, they are not exhaustiveand can include other suitable designs and systems that vary in designs,methodologies, and transduction systems (i.e., assays) known to those ofskill in the art. In other words, the examples are provided for thepurpose of illustration only, and are not intended to be limiting unlessotherwise specified. Thus, the invention should in no way be construedas being limited to the following examples, but rather, should beconstrued to encompass any and all variations which become evident as aresult of the teaching provided herein.

EXAMPLE 1

197.4 g of 2-octyl cyanoacrylate was mixed with 0.20 g of poly vinylpyrrolidone (PVP) under vacuum for 2 hours and solid powder was removedby filtration. The resulting solution was mixed with certain amounts ofstabilizer, BHA, and colorant, D & C Violet under vacuum for a minimumof 0.5 hour. A sulfur dioxide solution in 2-octyl cyanoacrylate wascharged into the solution to further stabilize the cyanoacrylatecomposition. The resulting purple solution was then filtered with amicrometer filter to yield the activated 2-octyl cyanoacrylate adhesivecomposition.

EXAMPLE 2

27 pounds of the activated 2-octyl cyanoacrylate was charged intostainless steel container equipped with the mechanical agitator. 0.12 gof SO₂ solution (5.8%) in 2-octyl cyanoacrylate was added to thecontainer and stirred for a minimum of 0.5 hour. 3.3 g of 18-crown-6 wasdissolved in 30 mL of 2-octyl cyanoacrylate in microwave, which wasadded to the bulk solution of 2-octyl cyanoacrylate in the stainlesssteel container and stirred for a minimum of 0.5 hour. After thefiltration, the resulting cyanoacrylate adhesive composition wassubjected to viscosity, set time, bond strength and accelerated agingtests (see Table 3). The bond strength measured for the samples at day 0and day 12 are 773.9, and 723.2 lbs/inch² respectively.

TABLE 3 Set time and viscosity results of examples 2 and 3. Day 0 DaySDay 9 Day 12 Set Set Set Set Aging time Viscosity time Viscosity timeViscosity time Viscosity condition (s} (cps) (s) (cps) (s) (cps) (s)(cps) Example 2 12 days 22 4.35 20 4.56 18 4.78 28 5.65 80° C. Example 312 days 35 5.43 33 4.99 24 6.30 38 6.52 80° C.

EXAMPLE 3

18 pounds of the activated 2-octyl cyanoacrylate was charged intostainless steel container equipped with the mechanical agitator. 0.078 gof SO₂ solution (5.8%) in 2- octyl cyanoacrylate was added to thecontainer and stirred for a minimum of 0.5 hour. 1.5 g of 18-crown-6 wasdissolved in 30 mL of 2-octyl cyanoacrylate in microwave, which wasadded to the bulk solution of 2-octyl cyanoacrylate in the stainlesssteel container and stirred for a minimum of 0.5 hour. After thefiltration, the resulting cyanoacrylate adhesive composition wassubjected to viscosity, set time, bond strength and accelerated agingtests (see Table 3). The bond strength measured for the samples at day 0and day 12 are 714.5, and 703.1 lbs/inch² , respectively.

EXAMPLE 4

864.4 g of the activated 2-octyl cyanoacrylate was put into 1 L ofopaque polyethylene bottle. 0.142 g of SO₂ solution (5.8%) in 2-octylcyanoacrylate was added to the container and stirred for a minimum of 1hour.

EXAMPLE 5

To a polyethylene bottle, 30.8 g of 2-octyl cyanoacrylate from example 4was mixed with 98.6 mg of 18-crown-6 and stirred at room temperature for2 hours. The sample was subjected to the accelerated aging test at 80°C. The average set time for the samples at day 0, day 6, and day 12 are6.7, 7.3, and 9.4 s, respectively. The average viscosity for the samplesat day 0, day 6, and day 12 are 3.27, 2.86, and 28.8 cps, respectively.

EXAMPLE 6

To a polyethylene bottle, 30.1 g of 2-octyl cyanoacrylate from example 4was mixed with 72.4 mg of 18-crown-6 and stirred at room temperature for2 hours. The sample was subjected to the accelerated aging test at 80°C. The average set time for the samples at day 0, day 6, and day 12 are8.3, 9, and 14 s, respectively. The average viscosity for the samples atday 0, day 6, and day 12 are 2.86, 2.86, and 24.3 cps, respectively.

EXAMPLE 7

To a polyethylene bottle, 30.9 g of 2-octyl cyanoacrylate from example 4was mixed with 30.9 mg of 18-crown-6 and stirred at room temperature for2 hours. The sample was subjected to the accelerated aging test at 80°C. The average set time for the samples at day 0, day 6, and day 12 are14.7, 14.7, and 19.3 seconds, respectively. The average viscosity forthe samples at day 0, day 6, and day 12 are 3.06, 3.06, and 20.4 cps,respectively.

EXAMPLE 8

To a polyethylene bottle, 30.5 g of 2-octyl cyanoacrylate from example 4was mixed with 21.4 mg of 18-crown-6 and stirred at room temperature for2 hours.

EXAMPLE 9

In a polyethylene bottle, 4.4 g of 2-octyl cyanoacrylate compositionfrom example 8 was diluted to 30.8 g by 2-octyl cyanoacrylatecomposition from example 4 and stirred at room temperature for 2 hours.The sample was subjected to the accelerated aging test at 80° C. Theaverage set time for the samples at day 0, day 6, and day 12 are 33,35.3, and 39 seconds, respectively. The average viscosity for thesamples at day 0, day 6, and day 12 are 2.65, 2.65, and 9.19 cps,respectively.

EXAMPLE 10

In polyethylene bottle, 0.616 g of 2-octyl cyanoacrylate compositionfrom example was diluted to 30.8 g by 2-octyl cyanoacrylate compositionfrom example 4 and stirred at room temperature for 2 hours. The samplewas subjected to the accelerated aging test at 80° C. The average settime for the samples at day 0, day 6, and day 12 are 70.3, 73.7, and 75seconds, respectively. The average viscosity for the samples at day 0,day 6, and day 12 are 2.87, 2.65, and 3.06 cps, respectively.

EXAMPLE 11

473.4 g of the activated 2-octyl cyanoacrylate was put into 1L of opaquepolyethylene bottle. 4.5 mg of SO₂ solution (5.8%) in 2-octylcyanoacrylate was added to the container and stirred for a minimum of 1hour.

EXAMPLE 12

To a polyethylene bottle, 30.1 g of 2-octyl cyanoacrylate from example11 was mixed with 96.5 mg of 18-crown-6 and stirred at room temperaturefor 2 hours. The sample was subjected to the accelerated aging test at80° C. The average set time for the samples at day 0, day 6, and day 12are 6.7, 6.3, and 7.7 seconds, respectively. The average viscosity forthe samples at day 0, day 6, and day 12 are 2.86, 3.47, and 11.4 cps,respectively.

EXAMPLE 13

To a polyethylene bottle, 30.1 g of 2 octyl cyanoacrylate from example11 was mixed with 48.3 mg of 18-crown-6 and stirred at room temperaturefor 2 hours. The sample was subjected to the accelerated aging test at80° C. The average set time for the samples at day 0, day 6, and day 12are 10, 9.7, and 11 seconds, respectively. The average viscosity for thesamples at day 0, day 6, and day 12 are 3.06, 3.27, and 7.33 cps,respectively.

EXAMPLE 14

To a polyethylene bottle, 29.9 g of 2-octyl cyanoacrylate from example11 was mixed with 29.9 mg of 18-crown-6 and stirred at room temperaturefor 2 hours. The sample was subjected to the accelerated aging test at80° C. The average set time for the samples at day 0, day 6, and day 12are 12.7, 11, and 12.3 seconds, respectively. The average viscosity forthe samples at day 0, day 6, and day 12 are 2.65, 3.24, and 3.68 cps,respectively.

EXAMPLE 15

To a polyethylene bottle, 30.0 g of 2-octyl cyanoacrylate from example11 was mixed with 8.10 mg of 18-crown-6 and stirred at room temperaturefor 2 hours. The sample was subjected to the accelerated aging test at80° C. The average set time for the samples at day 0, day 6, and day 12are 17, 15, and 17.3 seconds, respectively. The average viscosity forthe samples at day 0, day 6 and day 12 are 2.87, 2.65, and 3.27 cps,respectively.

EXAMPLE 16

To a polyethylene bottle, 19.6 g of 2-octyl cyanoacrylate from example11 was mixed with 9.9 mg of 18-crown-6 and stirred at room temperaturefor 2 hours.

EXAMPLE 17

In a polyethylene bottle, 2.4 g of 2-octyl cyanoacrylate compositionfrom example 16 was diluted to 30 g by 2-octyl cyanoacrylate compositionfrom example 11 and stirred at room temperature for 2 hours. The samplewas subjected to the accelerated aging test at 80° C. The average settime for the samples at day 0, day 6, and day 12 are 42.3, 55.3, and 47seconds, respectively. The average viscosity for the samples at day 0,day 6, and day 12 are 2.87, 3.27, and 2.65 cps, respectively.

EXAMPLE 18

In a polyethylene bottle, 0.59 g of 2-octyl cyanoacrylate compositionfrom example 16 was diluted to 30 g by 2-Octyl cyanoacrylate compositionfrom example 11 and stirred at room temperature for 2 hours. The samplewas subjected to the accelerated aging test at 80° C. The average settime for the samples at day 0, day 6, and day 12 are 53.7, 67, and 61.7seconds, respectively. The average viscosity for the samples at day 0,day 6, and day 12 are 3.06, 2.87, and 3.47 cps, respectively.

EXAMPLE 19

33.4 pounds of the activated 2-octyl cyanoacrylate was charged intostainless steel container equipped with the mechanical agitator. 0.144 gof SO₂ solution (5.8%) in 2-octyl cyanoacrylate was added to thecontainer and stirred for a minimum of 0.5 hour. 4.06 g of 18-crown-6was added to the bulk solution of 2-octyl cyanoacrylate in the stainlesssteel container and stirred for a minimum of 0.5 hour. After thefiltration, the resulting cyanoacrylate adhesive composition wassubjected to viscosity, set time, bond strength and accelerated agingtests.

EXAMPLE 20

To a polyethylene bottle, 30.8 g of 2-octyl cyanoacrylate compositionfrom example 19 was mixed with 90.5 mg of 18-crown-6 and stirred at roomtemperature for 2 hours. The sample was subjected to the acceleratedaging test at 80° C. The average set time for the samples at day 0, day6, and day 12 are 8.67, 11, and 11.3 seconds, respectively. The averageviscosity for the samples at day 0, day 6, and day 12 are 3.06, 2.86,and 55.2 cps, respectively.

EXAMPLE 21

To a polyethylene bottle, 30.8 g of 2-octyl cyanoacrylate compositionfrom example 19 was mixed with 41.3 mg of 18-crown-6 and stirred at roomtemperature for 2 hours. The sample was subjected to the acceleratedaging test at 80° C. The average set time for the samples at day 0, day6, and day 12 are 17, 24.3, and 22 seconds, respectively. The averageviscosity for the samples at day 0, day 6, and day 12 are 2.45, 2.65,and 23.8 cps, respectively.

EXAMPLE 22

Shelf life (real time) of 2-octyl cyanoacrylate adhesives with curespeed enhancer is under way and set time and viscosity data have beenaccumulated up to 9 months. Data for 2 year shelf life will be obtainedby the end of May of 2008. The average set time for the samples at month0, month 3, month 8, and month 10 are 35, 22, 35, and 31 seconds,respectively. The average viscosity for the samples at month 0, month 3,month 8, and month 10 are 5.11, 4.49, 8.97 and 10 cps, respectively.

EXAMPLE 23

Heat of polymerization of 2-octyl cyanoacrylate adhesives with curespeed enhancer was measured with DSC. Samples were transferred to analuminum DSC pan via disposable pipette from a freshly openedapplicator. Each sample was heated from 30° C. to

300° C. at a rate of 10° C./min in an atmosphere of nitrogen flowing ata rate of 20 cc/min. In each product there appears to be a two stagepolymerization which cannot be accurately separated using a temperatureramp of 10° C. per minute. The average heat of polymerization is 225J/g.

Throughout this application, various publications, including UnitedStates patents, are referenced by author and year and patents by number.Full citations for the publications are listed below. The disclosures ofthese publications and patents in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

The invention has been described in an illustrative manner, and it is tobe understood that the terminology which has been used is intended to bein the nature of words of description rather than of limitation.

Obviously, many modifications and variations of the present inventionare possible in light of the above teachings. It is, therefore, to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described.

1. (canceled)
 2. A sterilized cyanoacrylate adhesive composition,comprising 99% or more by weight, based on the weight of the adhesivecomposition, of 2-octyl cyanoacrylate, mixed together with free radicalstabilizer, anionic vapor phase stabilizer, and 100 to 1000 parts permillion, based on the weight of the adhesive composition, of a18-crown-6 crown ether, wherein the composition is sterilized byirradiation, and wherein the sterilized cyanoacrylate adhesivecomposition does not cure upon sterilization.
 3. The sterilizedcyanoacrylate adhesive composition of claim 2, wherein the adhesiveremains fluid following storage for twelve days at 80° C.
 4. Thesterilized cyanoacrylate adhesive composition of claim 2, wherein theanionic vapor phase stabilizer is present in the composition at aconcentration of less than 20 parts per million.
 5. The sterilizedcyanoacrylate adhesive composition of claim 2, wherein the free radicalstabilizer is butylated hydroxyl anisole.
 6. The sterilizedcyanoacrylate adhesive composition of claim 2, wherein the anionic vaporphase stabilizer is sulfur dioxide.
 7. The sterilized cyanoacrylateadhesive composition of claim 2, further comprising therapeutic-loadednanoparticles.
 8. The sterilized cyanoacrylate adhesive composition ofclaim 2, wherein the composition has been treated with a particulateagent selected from the group consisting of vinyl pyrrolidone polymersand co-polymers.
 9. The sterilized cyanoacrylate adhesive composition ofclaim 2, wherein the irradiation is gamma irradiation, electron beamirradiation, microwave irradiation, or ultraviolet radiation.
 10. A kit,comprising the sterilized cyanoacrylate adhesive composition of claim 2and an applicator.
 11. The kit of claim 10, wherein said sterilizedcyanoacrylate adhesive composition has been treated with a particulateagent chosen from the group consisting of vinyl pyrrolidone polymers andco-polymers.
 12. The kit of claim 10, wherein the anionic vapor phasestabilizer is present in the composition at a concentration of less than20 parts per million.
 13. The kit of claim 10, wherein the free radicalstabilizer is butylated hydroxyl anisole and said anionic vapor phasestabilizer is sulfur dioxide.
 14. The kit of claim 10, wherein thesterilized cyanoacrylate adhesive composition further comprisestherapeutic-loaded nanoparticles.
 15. A method of making the sterilizedcyanoacrylate adhesive composition of claim 2, comprising mixing 99% ormore by weight, based on the weight of the adhesive composition, of2-octyl cyanoacrylate with a free radical stabilizer, an anionic vaporphase stabilizer, and 100 to 1000 parts per million, based on the weightof the adhesive composition, of a 18-crown-6 crown ether to form acyanoacrylate adhesive composition, and sterilizing the composition byirradiating the composition, wherein the sterilized cyanoacrylateadhesive composition does not cure upon sterilization.
 16. The method ofclaim 15, wherein the adhesive remains fluid following storage fortwelve days at 80° C.
 17. The method of claim 15, further comprisingtreating the composition with a particulate agent selected from thegroup consisting of vinyl pyrrolidone polymers and co-polymers.
 18. Themethod of claim 15, wherein the anionic vapor phase stabilizer ispresent in the composition at a concentration of less than 20 parts permillion.
 19. The method of claim 15, wherein the free radical stabilizeris butylated hydroxyl anisole and said anionic vapor phase stabilizer issulfur dioxide.
 20. The method of claim 15, further comprising mixingtherapeutic-loaded nanoparticles together with the cyanoacrylateadhesive composition.
 21. The method of claim 15, wherein saidsterilizing comprises irradiating the composition with gammairradiation, electron beam irradiation, microwave irradiation, orultraviolet radiation.
 22. A method of sealing tissue, comprisingapplying the sterilized cyanoacrylate adhesive composition of claim 2 toa patent's tissue, and allowing the sterilized composition to cure.